Protease activated receptors (PARs) are a family of four G protein coupled receptors numbered PAR-1 to PAR-4. Since its discovery in the early 90's, PAR-1 has been found in many tissues including the brain where it is found on several cell types including neurons, astrocytes and microglia. The first functions of PAR-1 described in neurons and glia involved cell survival and cell death. This dual effect is concentration dependent where at high levels of PAR-1 activation deleterious effects are seen and at lower levels protective effects are seen. PAR-1 carries all determinants required for thrombin recognition.
Many neurological diseases are known to be associated with increased inflammation and over activation of protease activated receptors (PARs) by protein factors of the coagulation cascade. This include, neuropathy which is commonly caused by diabetes mellitus, occurring in 60% of all diabetic patients.
Many studies have suggested that thrombin plays a role in angiogenesis and its inhibition reduces edema. Glioblastoma multiform, (GBM) is a rapidly growing brain tumor resulting in high mortality within month. Several processes characterize GBM including increased angiogenesis, edema formation and enhanced tumor cell proliferation.
US 2009/0281100 and US 2004/0092535 disclose a method of inhibiting a serine/threonine kinase using benzimidazole quinolinones, wherein the serine/threonine kinase is PAR-1, for treating diabetes, noninsulin dependent diabetes mellitus, Alzheimer's disease, bipolar disorder, cancer, autoimmune diseases and organ transplant rejection.
US 2012/0232097 and US 2009/0176803 disclose cinnamoyl-piperazine derivatives as PAR-1 antagonists and uses thereof for treating and/or preventive arterial/venous thrombosis, acute coronary syndromes, restenosis, stable angina, heart rhythm disorders, myocardial infarction, hypertension, heart failure, stroke, inflammatory disorders, pulmonary diseases, gastrointestinal diseases, fibrosis development in chronic liver disease patients, cancer and skin diseases.
U.S. Pat. Nos. 8,232,295 and 7,842,716 disclose methods for treating and/or preventing vascular events by inhibiting PAR-1 and/or PAR-4 using statins.
US 2007/0142272 discloses use of an activated protein C (APC), prodrug and/or a variant thereof as agonist of PAR-1 and/or PAR-3 and/or endothelial protein C receptor (EPCR) for providing neuroprotection, treating neurodegenerative disease and improving stress or injury.
Despite efforts made in the field, there remains an unmet need in the art for potent inhibitors that inhibit or prevent over activation of PARs, especially, PAR-1.